Evaluation of Genetic Diversity, Drug Resistance Mutational and Cytokine Patterns on Hepatotoxicity Markers among Hiv Patients in Northwest Region, Cameroon
Lem, Edith Abongwa
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Highly active anti-retroviral therapy (HAART) has been known to cause hepatotoxicity despite its benefit to improve the morbidity and mortality associated with HIV infections. However, the impact of HAART on HIV subtypes, drug resistance mutations and cytokine profiles, is not yet fully elucidated especially in the Northwest Region (NWR) of Cameroon. Therefore, this study was carried out with aim of determining the effect of HIV-1 subtypes, drug resistance mutations, cytokine profiles and risk factors on hepatotoxicity markers among HIV-1 drug naïve adults in the NWR of Cameroon. This was a longitudinal study conducted from February to November 2016 and newly diagnosed HIV-1 drug-naive patients were recruited into the study. Stratified and simple random sampling techniques were used in selecting the five study sites. Blood samples were collected prior to HAART initiation Day (D) 0 and at D30 and D180. The participants were placed on either Tenofovir (TDF) + Lamivudine (3TC) + Efavirenz (EFV) or Zidovudine (AZT) + 3TC + Nevirapine (NVP) or AZT+3TC+EFV regimens. Serum levels of alanine aminotransferases (ALT), aspartate aminotransferases (AST) and alkaline phosphatase (ALP) were analyzed. Human Th1/Th2/Th17 cytokines were measured using a cytometric bead array assay. Genotypic and transmitted drug resistance (TDR) analyses were performed by sequencing HIV virus using an in-house protocol. Data were analyzed using SPSS vs. 23 and Graph pad prism 6. HIV-1 subtypes were determined phylogenetically using MEGA vs. 7 while TDR and resistance-associated mutations (RAMs) were identified using the Stanford HIVDR interpretation program. The level of significance was set at 5%. In all, 100 individuals participated in the study with a mean (age range) of 36.5 (18-61) years. Of this, 37(37%) and 49(49%) patients presented with hepatotoxicity while 15% and 28% of patients had severe hepatotoxicity at D30 and D180 respectively. Serum levels of ALT, AST and ALP increased significantly (p<0.05) with increased treatment duration and in patients on AZT+3TC+NVP treatment. Multivariate analysis showed that age <30 years, low BMI, low monthly income and the use of AZT+3TC+NVP regimen were independent risk factors for severe hepatotoxicity. Mean interleukin (IL)-6 and IL-17A, were significantly (p<0.05) high in patients with hepatotoxicity compared to patients without hepatotoxicity at D30 and D180. HIV-1 subtype revealed that CRF02 _AG (75.3.0%) was the most predominant subtype. The prevalence of hepatotoxicity was highest at 70.3% (26/37) among individual harboring CRF02_AG virus. This study shows that 9 (11.1%) patients were infected with HIV variants that carried RAMs associated with NRTI; 8.6% (7/81), NNRTI; 4.9% (4/81) and PI; 1.2% (1/81). Seven of the nine patients with TDR developed hepatotoxicity of different grades at D180. Thus the use of NVP based regimen should not be recommended for patients less than 30 years and with low baseline BMI. IL-6 and IL-17A seem to play a significant role in the pathophysiology of hepatotoxicity. CRF02_AG was the most predominant HIV strain. Despite the sample size, these findings highlight a caution in the management of hepatotoxicity and the need for continuous surveillance for TDR.